WO2016002717A1 - Promoteur de l'ostéogenèse - Google Patents

Promoteur de l'ostéogenèse Download PDF

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Publication number
WO2016002717A1
WO2016002717A1 PCT/JP2015/068683 JP2015068683W WO2016002717A1 WO 2016002717 A1 WO2016002717 A1 WO 2016002717A1 JP 2015068683 W JP2015068683 W JP 2015068683W WO 2016002717 A1 WO2016002717 A1 WO 2016002717A1
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WIPO (PCT)
Prior art keywords
promoting material
bone
bone formation
amino acid
self
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PCT/JP2015/068683
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English (en)
Japanese (ja)
Inventor
圭 安藤
石黒　直樹
史郎 今釜
全哉 伊藤
康弘 横山
秀典 横井
永井　祐介
Original Assignee
国立大学法人名古屋大学
株式会社メニコン
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by 国立大学法人名古屋大学, 株式会社メニコン filed Critical 国立大学法人名古屋大学
Priority to US15/317,569 priority Critical patent/US10821136B2/en
Priority to CN202310424217.4A priority patent/CN116603103A/zh
Priority to JP2016521805A priority patent/JP6042038B2/ja
Priority to EP15815879.0A priority patent/EP3162374A4/fr
Priority to CN201580036020.7A priority patent/CN106573019A/zh
Publication of WO2016002717A1 publication Critical patent/WO2016002717A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/32—Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1875—Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K17/00—Carrier-bound or immobilised peptides; Preparation thereof
    • C07K17/14—Peptides being immobilised on, or in, an inorganic carrier
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the present invention relates to a bone formation promoting material. More specifically, the present invention relates to a bone formation promoting material including a self-assembling peptide and bone fragments.
  • the spine has not only the role of supporting the body from gravity but also the role of protecting the spinal cord, which is the central nervous system.
  • diseases that compress nerves such as the spinal cord (for example, cervical spondylotic myelopathy) and fractures of the spine are major problems.
  • spinal cord compression the bone that compresses the spinal cord must be excised.
  • the spine that has become unstable after excision is transplanted with bone collected from the subject and fixed using a metal such as a metal bolt or plate.
  • the basics of fracture treatment are reduction and fixation, and generally, a method of fixing with a metal and bone healing is taken.
  • a long fusion period of 2 to 3 months is required for limb fractures and half a year to 1 year or more for vertebral fractures.
  • the bone itself is weakened, so there are cases where the bone is fractured again before bone fusion is obtained, or the metal used for fixation is displaced.
  • a femoral neck fracture or vertebral fracture may require a bed rest, which may lead to disuse syndrome and require care.
  • An object of the present invention is to provide a bone formation promoting material that has high biological safety and can promote bone formation.
  • the osteogenesis promoting material of the present invention includes a self-assembling peptide capable of forming a ⁇ -sheet structure in an aqueous solution having a neutral pH, and a bone fragment.
  • the total charge at pH 7.0 of amino acid residues constituting this self-assembling peptide is not zero.
  • the self-assembling peptide is a self-assembling peptide consisting of the following amino acid sequence.
  • the osteogenesis promoter further comprises blood and / or blood-derived components.
  • the osteogenesis promoting material further includes an osteogenesis factor.
  • the osteogenesis promoting material is used in combination with a holding device for osteogenesis promoting material.
  • a holding device for osteogenesis promoting material is provided.
  • the holding device for osteogenesis promoting material of the present invention is used together with the osteogenesis promoting material.
  • the bone formation promoting material holder is made of a carbon-based material, an engineering resin, or a super engineering resin.
  • the osteogenesis promoting material of the present invention includes a self-assembling peptide and bone fragments capable of forming a ⁇ sheet structure in an aqueous solution having a neutral pH. Thereby, many starting points of bone formation are formed, and bone formation can be favorably promoted. Therefore, bone formation can be improved even in an elderly person whose strength and bone regeneration ability of the bone itself are reduced. Moreover, the osteogenesis promoting material of the present invention can induce osteogenesis without using cells or the like directly involved in osteogenesis.
  • the self-assembling peptide used in the present invention forms a ⁇ -sheet structure in an aqueous solution having a neutral pH, and the total charge at pH 7.0 of amino acid residues constituting the self-assembling peptide is not zero. Therefore, the bone formation promoting material of the present invention can exhibit sufficient strength at a neutral pH close to the biological environment. Furthermore, the bone formation promoting material can be fixed at a desired position by using an appropriate holding device such as the bone formation promoting material holding device of the present invention.
  • FIG. 4 shows photographs of the osteogenesis promoting material of Examples 1 to 3 and the osteogenesis promoting material of Comparative Example 1 after 14 days and 28 days of culture and ALP staining. It is the photograph of the external fixator used for preparation of a femur defect model. It is the photograph of the cage used for preparation of a femur defect model. It is the photograph of the femur of the mouse
  • FIG. 9 (a) is a photograph of the gel before adding the born chip of Example 5
  • FIG. 9 (b) is a photograph of the gel before adding the born chip of Example 6
  • FIG. 9 (c) is a comparative example. It is the photograph of the gel before 2 born chip addition.
  • FIG. 10 (a) is a photograph of the gel (bone formation promoting material) after addition of the born chip of Example 5
  • FIG. 10 (b) is the gel (bone formation promoting material) after addition of the born chip of Example 6.
  • FIG. 10 (c) is a photograph of the gel (bone formation promoting material) after adding the born chip of Comparative Example 2.
  • the osteogenesis promoting material of the present invention contains a self-assembling peptide capable of forming a ⁇ sheet structure in an aqueous solution having a neutral pH and a bone fragment.
  • the total charge at pH 7.0 of amino acid residues constituting this self-assembling peptide is not zero.
  • the osteogenesis promoter of the present invention further comprises blood and / or blood-derived components.
  • the osteogenesis promoting material of the present invention further includes an osteogenesis factor.
  • the storage elastic modulus (G ′) at 37 ° C. in the dynamic viscoelasticity measurement using the rotary rheometer of the osteogenesis promoting material of the present invention is, for example, 1 Pa to 5000 Pa, preferably 1 Pa to 4000 Pa, more preferably Is 1 Pa to 3000 Pa. If the storage elastic modulus is within the above range, it can be used in combination with the bone formation promoting material holding device of the present invention described later, and bone formation can be preferably promoted.
  • the storage elastic modulus as used in this specification means the value when the angular frequency when frequency change measurement is performed is 1 radian / second.
  • any suitable peptide that can spontaneously assemble through the interaction of peptide molecules in an aqueous solution to form a gel can be used.
  • the self-assembling peptide used in the present invention can form a ⁇ sheet structure at a neutral pH. More specifically, a fibrous molecular assembly is formed spontaneously through interaction between peptide molecules in an aqueous solution, and a three-dimensional network structure is developed by the interaction between the molecular assemblies.
  • Peptides that can form gels can be preferably used. Examples of the interaction between peptide molecules include electrostatic interactions such as hydrogen bonds, ionic interactions, van der Waals forces, and hydrophobic interactions.
  • neutral pH (neutral region) means pH 5.0 to 8.0, preferably pH 5.5 to 7.5, more preferably pH 6.0 to 7.0, Preferably it refers to the region of pH 7.0.
  • the amino acid constituting the self-assembling peptide may be an L-amino acid or a D-amino acid. L-amino acids are preferred. Moreover, a natural amino acid may be sufficient and a non-natural amino acid may be sufficient. Natural amino acids are preferred because they are available at low cost and facilitate peptide synthesis.
  • the total sum of charges at pH 7.0 of amino acid residues constituting the self-assembling peptide is not zero.
  • the sum of the charges is preferably ⁇ 3 to ⁇ 1 or +1 to +3, and more preferably ⁇ 3, ⁇ 2, +2 or +3.
  • the charge of the self-assembling peptide at each pH can be performed by a program available on the website of PROTEIN CALCULATOR v3.4 (http://protocol.sourceforge.net/).
  • a 1 to a 4 are basic amino acid residues
  • b 1 to b 6 are uncharged polar amino acid residues and / or hydrophobic amino acid residues, at least of which 5 are hydrophobic amino acid residues
  • c 1 and c 2 are acidic amino acid residues
  • d is a hydrophobic amino acid residue.
  • a 1 to a 4 are basic amino acid residues.
  • the basic amino acid is preferably arginine, lysine or histidine, more preferably arginine or lysine. This is because these amino acids are strongly basic.
  • a 1 to a 4 may be the same amino acid residue or different amino acid residues.
  • b 1 to b 6 are uncharged polar amino acid residues and / or hydrophobic amino acid residues, and at least 5 of them are hydrophobic amino acid residues.
  • the hydrophobic amino acid is preferably alanine, leucine, isoleucine, valine, methionine, phenylalanine, tryptophan, glycine or proline.
  • the uncharged polar amino acid is preferably tyrosine, serine, threonine, asparagine, glutamine, or cysteine. This is because these amino acids are easily available.
  • b 3 and b 4 are each independently any suitable hydrophobic amino acid residue, more preferably a leucine residue, an alanine residue, a valine residue, or an isoleucine residue, particularly preferably Is a leucine residue or an alanine residue.
  • b 1 to b 6 are all hydrophobic amino acid residues. This is because the self-assembling peptide preferably forms a ⁇ -sheet structure and can self-assemble. More preferably, b 1 to b 6 are each independently a leucine residue, an alanine residue, a valine residue, or an isoleucine residue, and more preferably a leucine residue or an alanine residue. In a preferred embodiment, 4 or more of b 1 to b 6 are leucine residues, more preferably 5 or more of them are leucine residues, and more preferably all are leucine residues.
  • c 1 and c 2 are acidic amino acid residues.
  • the acidic amino acid is preferably aspartic acid or glutamic acid. This is because these amino acids are easily available.
  • c 1 and c 2 may be the same amino acid residue or different amino acid residues.
  • d is a hydrophobic amino acid residue.
  • d is preferably an alanine residue, a valine residue, a leucine residue, or an isoleucine residue.
  • two of the three consecutive amino acid residues of b 3 , d, b 4 are leucine residues and the rest are alanine residues.
  • any of b 3 , d, and b 4 may be an alanine residue.
  • all three consecutive amino acid residues of b 3 , d, and b 4 are leucine residues.
  • n-RLDLRLALRLLDLR-c SEQ ID NO: 1
  • n-RLDLRLLLLRLDLR-c SEQ ID NO: 2
  • n-RADLRLALRLLDLR-c SEQ ID NO: 3
  • n-RLDLRLALLRLDA-c SEQ ID NO: 4
  • n-RADLRLLLRLLDLR-c SEQ ID NO: 5
  • n-RADLRLLLRLDA-c SEQ ID NO: 6
  • n-RLDLRLALLLDLR-c SEQ ID NO: 7
  • n-RLDLRLLARLDLR-c SEQ ID NO: 8
  • Another self-assembling peptide that can be preferably used in the present invention is a peptide described in WO2007 / 000979, that is, a self-assembling peptide having a polar amino acid residue and a nonpolar amino acid residue (hydrophobic amino acid residue) Wherein the polar amino acid residue includes an acidic amino acid residue and a basic amino acid residue, and in the neutral region, the sum of the charge of the acidic amino acid residue and the charge of the basic amino acid residue is 0. And a self-assembling peptide capable of forming a ⁇ -sheet structure in which only the nonpolar amino acid residues are arranged on one surface when self-assembled in an aqueous solution.
  • peptides containing acidic amino acid residues, basic amino acid residues, and uncharged polar amino acids are preferred as polar amino acids.
  • Preferred specific examples of such self-assembling peptides are exemplified below.
  • n-RASARADARASARADA-c SEQ ID NO: 9
  • n-RANARADARANARADA-c SEQ ID NO: 10
  • n-RAAARADAARAAARADA-c SEQ ID NO: 11
  • n-RASARADARADARASA-c SEQ ID NO: 12
  • n-RADARASARASARADA-c SEQ ID NO: 13
  • n-RASARASARASARADA-c SEQ ID NO: 14
  • n-RASARADARASA-c SEQ ID NO: 15
  • n-KASAKAEAKASAKAEA-c SEQ ID NO: 16
  • n-SAEAKAEASAEAKAEA-c SEQ ID NO: 17
  • n-KLSLKLDLKLSL-c SEQ ID NO: 18
  • n-KLALKLDLKLAL-c SEQ ID NO: 19
  • the self-assembling peptide can be manufactured by any appropriate manufacturing method. Examples thereof include a chemical synthesis method such as a solid phase method such as the Fmoc method or a liquid phase method, and a molecular biological method such as gene recombinant expression.
  • the self-assembling peptide may be subjected to any appropriate modification depending on the purpose and the like.
  • the site where the modification is performed is not particularly limited, and examples thereof include an N-terminal amino group, a C-terminal carboxyl group, or both of the self-assembling peptide.
  • any appropriate modification can be selected as long as the modified peptide has the ability to self-assemble.
  • introduction of protecting groups such as acetylation of N-terminal amino group and amidation of C-terminal carboxyl group; introduction of functional groups such as alkylation, esterification or halogenation; hydrogenation; monosaccharide, disaccharide, oligo
  • Introduction of sugar compounds such as sugars or polysaccharides
  • introduction of lipid compounds such as fatty acids, phospholipids or glycolipids
  • introduction of amino acids or proteins introduction of DNA; introduction of compounds having other physiological activities.
  • Only one type of modification may be performed, or two or more types may be combined.
  • the N-terminus of an added peptide having a desired amino acid introduced at the C-terminus of the self-assembling peptide may be acetylated and the C-terminus amidated.
  • the number of amino acids to be introduced is preferably 1 to 180, more preferably 1 to 50, still more preferably 1 to 30, particularly preferably 1 to 10, and most preferably 1. ⁇ 5. If the number of amino acid residues to be introduced exceeds 180, the self-organizing ability may be impaired.
  • the osteogenesis promoting material of the present invention may contain only one kind of self-assembling peptide, or may contain two or more kinds of self-assembling peptides.
  • the concentration of the self-assembling peptide in the osteogenesis promoting material of the present invention can be appropriately set according to the composition, use, and the like.
  • the concentration of the self-assembling peptide is preferably 0.1% by weight to 5.0% by weight, more preferably 0.1% by weight to 3.0% by weight, and still more preferably 0.1% by weight to 2.0% by weight. %. If it is the density
  • the bone fragment used in the present invention may be the bone of the patient who is treated using the bone formation promoting material of the present invention, or may be the bone of another person. Moreover, the bone extract
  • a bone fragment excised for decompression can be used as the bone used as the bone fragment.
  • the collected bone piece may be used as it is, or may be used after any appropriate pretreatment.
  • pretreatment include washing by irrigating with phosphate buffered saline (PBS), drying, and the like.
  • PBS phosphate buffered saline
  • the size of the bone fragment is not particularly limited, and may be any appropriate size depending on the site to which the bone formation promoting material is applied.
  • the collected bone fragment may be used as it is, may be cut into a desired thickness, or may be used after being processed into any appropriate size (for example, powder).
  • the size of the bone fragment is, for example, 0.5 mm to 5.0 mm, preferably 1.0 mm to 4.0 mm.
  • the size of the bone fragment is, for example, 0.01 mm to 0.5 mm, preferably 0.02 mm to 0.4 mm. is there.
  • the size of the bone fragment is preferably 0.03 mm to 0.3 mm, more preferably 0.04 mm to 0.2 mm. When the size of the bone fragment is within the above range, the bone formation can be more preferably promoted. In this specification, the size of a bone fragment refers to the size of the maximum size portion of one bone fragment.
  • the bone fragment can be processed into a desired size by any appropriate means.
  • a crushing mill etc. are mentioned.
  • the bone fragment content in the osteogenesis promoting material of the present invention is preferably 1 to 100 parts by weight, more preferably 1 to 90 parts by weight with respect to 100 parts by weight of the self-assembled peptide gel. is there.
  • standard self-organization peptide gel means the gel which consists only of self-assembly peptide and water.
  • the osteogenesis promoting material of the present invention preferably further contains blood and / or blood-derived components.
  • blood-derived components include red blood cells, white blood cells, platelets, plasma, and the like. These blood-derived components may be used alone or in combination of two or more.
  • the blood and / or blood-derived component may be collected from a patient or collected from another person.
  • blood products such as whole blood products, erythrocyte products, plasma products, and platelet products may be used.
  • the concentration of blood and / or blood-derived components in the bone formation promoting material of the present invention is preferably 0.001 ppm to 1000 ppm, more preferably 0.01 ppm to 1000 ppm.
  • concentration of blood and / or blood-derived components is within the above range, bone formation can be promoted more suitably.
  • the osteogenesis promoting material of the present invention further contains a bone morphogenetic protein (BMP).
  • BMP bone morphogenetic protein
  • the osteogenesis promoting material of the present invention can further promote osteogenesis.
  • Specific examples of osteogenic factors include BMP2 / 4 BMP such as BMP2 and BMP4, BMP5, BMP6, BMP7, BMP8a, BMP8b and other OP-1 BMP, BMP9, BMP10 and other BMP9 BMP, GDF5, GDF6, Examples include GDF5-based BMP such as GDF7.
  • BMP-2 is preferable because it can favorably promote bone formation.
  • the bone morphogenetic factor may be appropriately modified within a range having the same bone formation promoting effect as the above bone morphogenetic factor.
  • the osteogenic factors may be used alone or in combination of two or more. Since these human BMPs have already been cloned, they can be obtained by genetic engineering techniques based on their nucleotide sequences.
  • the concentration of the bone formation factor in the osteogenesis promoting material of the present invention is usually 0.001 ppm to 1000 ppm, preferably 0.01 ppm to 1000 ppm. If it is the said density
  • the osteogenesis promoting material of the present invention may further contain a physiologically active substance other than the above osteogenic factor.
  • physiologically active substance that can be included in the osteogenesis promoting material of the present invention include differentiation regulators that induce or promote differentiation of bone or cartilage (eg, TGF- ⁇ ); growth hormones; cell function regulators such as EGF and FGF; Immunity or inflammation-related factors such as interferon and interleukin;
  • the concentration of the physiologically active substance in the bone formation promoting material of the present invention is usually 0.001 ppm to 1000 ppm, preferably 0.01 ppm to 1000 ppm. If it is the said density
  • the osteogenesis promoting material of the present invention may further contain any appropriate additive as required.
  • additives include pH adjusters; buffers; isotonic agents; salts; amino acids; vitamins; alcohols; proteins; These additives may be used alone or in combination of two or more.
  • pH adjuster examples include hydrochloric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate and the like.
  • Buffers include phosphates such as phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate; boric acid, borax Borate salts such as sodium borate and potassium borate; citrate salts such as sodium citrate and disodium citrate; acetates such as sodium acetate and potassium acetate; Tris and HEPES.
  • phosphates such as phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate
  • boric acid borax Borate salts such as sodium borate and potassium borate
  • citrate salts such as sodium citrate and disodium citrate
  • acetates such as sodium acetate and potassium acetate
  • Tris and HEPES Tris and HEPES.
  • Isotonic agents include chlorides such as sodium chloride, potassium chloride, calcium chloride and magnesium chloride; monosaccharides such as glucose, fructose and galactose; disaccharides such as sucrose, trehalose, maltose and lactose; mannitol, sorbitol and the like Sugar alcohols; and the like.
  • any appropriate salt other than the additives exemplified above can be used.
  • examples thereof include sodium sulfate and magnesium sulfate.
  • the addition amount of the additive can be set to any appropriate value depending on the purpose and the like.
  • the osteogenesis promoting material of the present invention can be prepared by any appropriate method.
  • a self-assembling peptide gel can be prepared by mixing a self-assembling peptide, water, and other optional components, and then allowing to stand, and then mixing the gel and bone fragments.
  • the self-assembling peptide used in the present invention spontaneously assembles through interaction between peptide molecules in a solution to form a fibrous molecular assembly, and further continues to stand, whereby the molecular assembly Due to the interaction between them, a three-dimensional network structure develops to form a gel.
  • the standing time and the standing temperature can be appropriately set according to the administration subject, the concentration and type of the self-assembling peptide, and the like.
  • purified water such as ion exchange water or distilled water can be preferably used.
  • the self-assembled peptide gel and the bone pieces When using small bone pieces (for example, powdered bone pieces) as the bone pieces, it is preferable to mix the self-assembled peptide gel and the bone pieces because they can be uniformly dispersed.
  • a large bone fragment eg, a bone fragment of about 3 mm
  • the self-assembled peptide gel and the bone fragment may be mixed, or the gel and the bone fragment may be mixed. It is not necessary (only adding bone fragments in the gel).
  • the method for preparing the osteogenesis promoting material of the present invention may further include optional steps such as purification such as filtration; sterilization such as high-pressure steam sterilization, radiation sterilization, and dry heat sterilization;
  • the osteogenesis promoting material of the present invention is used together with a holding device for osteogenesis promoting material.
  • the bone formation promoting material has a sufficient strength at a neutral pH close to the in vivo environment.
  • the bone formation promoting material holding device is preferably a device having a net or mesh structure.
  • the holding device of the present invention can hold bone formation promotion without applying an excessive load to the administration target site. Therefore, for example, it can be used for elderly people whose strength of the bone itself has decreased without applying a burden to the bone. In the case of a fracture, it has been difficult to fix at a site having a complicated shape.
  • the holding device for osteogenesis promoting material of the present invention can use a net, it can follow a complex-shaped portion and can hold the osteogenesis promoting material satisfactorily.
  • An example of a device having a network structure is a stent.
  • the holding device for osteogenesis promoting material of the present invention is composed of a carbon-based material from the viewpoint of excellent biological safety. Any appropriate material can be used as the carbon-based material. Examples of the carbon-based material include carbon-based fibers and carbon nanotubes. As the carbon-based material, carbon-based fibers and carbon nanotubes are preferable.
  • any appropriate orthopedic implant product may be used as the holding device for the bone formation promoting material.
  • a cage, a screw, a rod, etc. are mentioned.
  • Orthopedic implant product can be composed of any suitable material.
  • suitable material for example, pure titanium, titanium alloy, titanium / nickel alloy, metal such as cobalt chrome, polycarbonate resin; polyacetal resin; polyester resin such as polyethylene terephthalate, polybutylene terephthalate, polycyclohexylene dimethyl terephthalate; polyphenylene ether resin; polyphenylene oxide; nylon 6, polyamide resins such as nylon 66 and aromatic polyamide; syndiotactic polystyrene; engineering resins such as ultrahigh molecular weight polyethylene, and polyphenylene sulfide resin, polysulfone resin, polyethersulfone resin, polyetheretherketone resin, polyarylate Resin, liquid crystal polymer, aromatic polyester resin, polyimide resin, polyamideimide resin, polyetherimide resin , Super engineering resins such as aramid resins. From the viewpoint of excellent heat resistance, mechanical strength, chemical resistance, and wear resistance, it is preferable to use an engineering resin or an orthopedic
  • the bone formation promoting material of the present invention is administered in the form of a gel, and a bone fragment having a small size (for example, a powdered bone fragment) can be preferably used. Therefore, it can be easily administered with a syringe or the like, and can be filled into a complicated or narrow administration target site (for example, a gap between bone cracks).
  • the osteogenesis promoting material of the present invention is used by gelling the osteogenesis promoting material and then administering (injecting) it to the administration target site.
  • the bone formation promoting material By gelling the bone formation promoting material, a state in which bone fragments are well dispersed in the bone formation promoting material can be maintained. Therefore, the bone formation promoting effect of the bone formation promoting material of the present invention can be suitably exhibited.
  • the injection of the bone formation promoting material into the administration target site can be performed using any appropriate means such as a syringe, a tube, and a pipette.
  • the self-assembled peptide contained in the bone formation promoting material of the present invention is excellent in biodegradability. Moreover, the bone fragment contained in the bone formation promoting material of the present invention advances bone formation and contributes to new bone formation. In addition, the bone fragment contained in the osteogenesis promoting material of the present invention remains at the administration target site even after decomposition of the self-assembling peptide, and can become a part of the fused bone.
  • the bone formation promoting material of the present invention is used together with the above-described holding device for bone formation promoting material.
  • a bone formation promoter is covered with a bone formation promoting material holding device in the form of a net, thereby forming bone formation. Promoters can be retained.
  • the holding device may be attached to a site to be administered.
  • a bone formation promoting material in the form of a gel may be administered to the administration target site in a state where a bone formation promoting material holding device (for example, a stent) is previously applied to the administration target site.
  • a bone formation promoting material holding device for example, a stent
  • the bone formation promoting material and the holding device can be integrated.
  • the self-assembling peptide contained in the osteogenesis promoting material of the present invention is excellent in biodegradability, it can be absorbed and decomposed over time, and bone fragments can become a part of fused bone. Therefore, after bone formation is completed, only the bone formation promoting material holding device can be removed as necessary.
  • the bone formation promoting material of the present invention may be used in combination with any appropriate fixing method as necessary.
  • the spine since the spine is a part that is constantly subjected to a large load, it needs to be fixed more stably. Therefore, for example, when the bone formation promoting material of the present invention is applied to a vertebral fracture, the bone formation promoting material of the present invention is used in combination with a plate or screw which is a conventional fixing method, so that the bone can be stably fixed. Bone formation can be promoted in this state, and bone union can be promoted in a more appropriate state.
  • the bone formation promoting material of the present invention can be used, for example, for repairing a defect site in bone tissue, periodontal tissue, and the like. Further, the bone formation promoting material of the present invention can promote bone formation while reducing the load on the bone. Therefore, it can be suitably applied to elderly people who are concerned about a decrease in bone strength and a decrease in bone regeneration function.
  • MC3T3-E1 cells are added to a 24-well plate at 50,000 cells / well. After seeding and culturing at room temperature for 24 hours, the medium is changed to a differentiation-inducing medium (the above medium further supplemented with 1% ascorbic acid, 0.2% hydrocortisone, and 2% ⁇ -glycerophosphate).
  • FBS fetal bovine serum
  • PenStrep penicillin streptomycin
  • self-assembling peptide gel C1 (manufactured by 3D Matrix, product name “Puramatrix TM ”, peptide concentration of Ac-RADARADARADARADA-CONH 2 was used.
  • the cells were cultured in the same manner except that 1% by weight gel was used, and the cells were cultured in the same manner without adding the self-assembling peptide gel. After 14 days and 28 days, the cells were subjected to ALP staining and RNA extraction, and the expression level in RNA was measured by RT-PCR. For phosphatase (ALP) staining, it was carried out in the manner described below.
  • ALP phosphatase
  • ALP staining Staining was performed using a Histofine SAB-PO® kit (manufactured by Nichirei Bioscience). The medium was aspirated from each well and washed 3 times with phosphate buffered saline (PBS). Subsequently, it was fixed with 4% paraformaldehyde (PFA), allowed to stand for 10 minutes, and then washed 3 times with PBS. Thereafter, it was permeabilized with 0.2% Triton X (registered trademark) -PBS solution, allowed to stand for 10 minutes, and washed 3 times with PBS.
  • PFA paraformaldehyde
  • blocking reagent I 3% methanol added with hydrogen peroxide
  • the mixture was allowed to stand for 10 to 15 minutes and washed 3 times with PBS.
  • blocking reagent II (10% goat normal serum) was added, and then allowed to stand for 10 minutes, and the first antibody (ALP antibody: abcam Anti-Alkaline Phosphatase, Tissue Non-Specific [EPR4477] antibody body ab 108337) was added. After standing for 2 hours, it was washed 3 times with PBS. Next, a second antibody (biotin-labeled anti-rabbit IgG antibody) was added, allowed to stand for 10 minutes, and washed 3 times with PBS.
  • ALP antibody abcam Anti-Alkaline Phosphatase, Tissue Non-Specific [EPR4477] antibody body ab 108337
  • an enzyme reagent peroxidase-labeled streptavidin
  • DAB substrate kit chromogenic substrate (reagent A)
  • substrate buffer reagent B
  • a drop of the reagent (reagent C) (a solution prepared by adding about 40 ⁇ l) and mixing without foaming) was added, and the mixture was allowed to stand for 5 to 20 minutes and washed with purified water three times. Subsequently, it was counterstained (hematoxylin), allowed to stand for 2 minutes, developed with water, allowed to stand for 10 minutes, and observed with a microscope.
  • FIGS. 1A to 1D show micrographs and ALP-stained photographs of cells after 0 days, 1 day, 7 days, 14 days, and 28 days of culture.
  • ALP which is a bone formation marker, is stained by ALP staining.
  • FIGS. 1A to 1D show micrographs and ALP-stained photographs of cells after 0 days, 1 day, 7 days, 14 days, and 28 days of culture.
  • ALP which is a bone formation marker
  • FIGS. 1A to 1D show micrographs and ALP-stained photographs of cells after 0 days, 1 day, 7 days, 14 days, and 28 days of culture.
  • ALP which is a bone formation marker
  • ALP bone formation markers
  • BMP-2 bone sialoprotein
  • BSP bone sialoprotein
  • osteocalcin Ostexix
  • osteopontin OSP
  • Example 1 Bone fragments (1 mm to 2 mm) were obtained by crushing the femur of the mouse using a pulverizer.
  • a self-assembled peptide gel 2 (manufactured by Menicon Co., Ltd., trade name: Panacea Gel SPG-178-204, peptide concentration: 0.4 w / w%) is placed on the obtained bone fragment and left to stand to form a gel.
  • the bone formation promoting material 1 was obtained.
  • the composition of the self-assembled peptide gel 2 is shown in Table 1.
  • the resulting bone formation promoting material was cultured using the medium MEM ⁇ , 10m% FBS, and 1% Anti-Anti.
  • FIG. 3 shows photographs of the osteogenesis promoting material after 14 days and 28 days of culture and photographs of the osteogenesis promoting material ALP stained.
  • Example 2 instead of the self-assembled peptide gel 2, a bone formation promoting material 2 was obtained in the same manner as in Example 1 except that 1 was used for the self-assembled peptide gel. The obtained bone formation promoting material 2 was cultured in the same manner as in Example 1.
  • FIG. 3 shows photographs of the osteogenesis promoting material after 14 days and 28 days of culture and photographs of the osteogenesis promoting material ALP stained.
  • Example 3 A bone formation promoting material 3 was obtained in the same manner as in Example 1 except that the self-assembled peptide gel 3 was used instead of the self-assembled peptide gel 2.
  • the composition of the self-assembled peptide gel 3 is shown in Table 1.
  • the obtained bone formation promoting material 3 was cultured in the same manner as in Example 1.
  • FIG. 3 shows photographs of the osteogenesis promoting material after 14 days and 28 days of culture and photographs of the osteogenesis promoting material ALP stained.
  • osteogenesis promoting materials 1 to 3 ALP-stained osteoblasts were confirmed.
  • the osteogenesis promoting material C1 the bone fragments were eroded, and osteoblasts were not confirmed.
  • Example 4 A bone defect part of 1 mm ⁇ 3 mm was prepared using a drill on the mouse femur to obtain a femur defect mouse.
  • the osteogenesis promoting material 1 obtained in Example 1 was transplanted into the femur defect portion of the obtained femur defect mouse. Two days, 7 days, 9 days, 14 days, and 21 days after transplantation, the femur portion of the mouse was incised, and the appearance of bone formation was observed.
  • bone healing of the defective part was progressing. Bone formation was clearly promoted in the bone formation promoting material 1 of the present invention as compared with the normal progress of bone fusion.
  • Preparation of femur defect model Anesthesia is performed by injecting 0.1-0.15 ml of somnopentyl (manufactured by Kyoritsu Pharmaceutical Co., Ltd.) into the abdominal cavity of a 10-week-old female rat (obtained from Chubu Scientific Materials). After the application, the thigh was incised and an external fixator (FIG. 4) was attached to the femur. Next, the femur in the middle of the part to which the external fixator was attached was shaved with an airtome to produce a bone defect portion of about 5 mm. (2) Production of born chip The femur collected from the rat was shaved with an airtome, and a bone chip was collected.
  • the collected born chip was stored at ⁇ 80 ° C. until use.
  • Self-assembled peptide gel 1 (manicon Corporation, trade name: Panacea Gel SPG-178-208, peptide concentration: 0.8 w / w%) in 80 ⁇ L of the above born chip 0.05 g
  • self-assembling peptide gel C1 (manufactured by 3D Matrix, product name “Puramatrix TM ”) or physiological saline was used in the same manner to obtain a bone formation promoting material. It was.
  • Each bone formation promoting material prepared in (3) above was made from PEEK cage (Yashima Proceed Co., Ltd., length: 5 mm, outer diameter: 5 mm, inner diameter: 3 mm, FIG. 5). Next, a cage into which a bone formation promoting material was injected was inserted into the femur defect portion of the femur defect mouse, and externally fixed as shown in FIG.
  • FIG. 7 shows an X-ray photograph
  • FIG. 8 shows a CT photograph of a femur defect portion that has been externally fixed using each bone formation promoting material.
  • the bone formation promoting material 1 obtained in Example 1 was applied to the femoral defect
  • bone regeneration was confirmed in the entire defect (SPG-178 in FIGS. 7 and 8).
  • the mouse to which the bone formation promoting material C1 was applied bone regeneration was confirmed only from both ends of the femur (PuraMatrix in FIGS. 7 and 8).
  • Example 5 Self-assembled peptide gel 3 was diluted with Milli-Q water to obtain a 1.0 w / w% aqueous solution. The obtained aqueous solution was dropped on a 24-well plate, and the properties of the gel were observed with a stereomicroscope (magnification 100 times). Further, the pH of the gel was measured with a pH test paper. After 5 mg of the born chip (rat femur) obtained in Test Example 2 was put in a test tube, 5 ⁇ L of the obtained aqueous solution was dropped. Subsequently, after stirring with a vortex mixer, air bubbles were removed with a centrifugal separator to obtain a bone formation promoting material 5. The properties of the obtained bone formation promoting material 5 were observed with a stereomicroscope (magnification 100 times). Further, the pH of the obtained bone formation promoting material was measured with a pH test paper.
  • Example 6 A bone formation promoting material 6 was obtained in the same manner as in Example 5 except that the self-assembled peptide gel 4 was used.
  • the composition of the self-assembled peptide gel 4 is shown in Table 1.
  • the properties and pH of the gel before adding the born chip, and the properties and pH of the bone formation promoting material 6 were evaluated in the same manner as in Example 5.
  • Bone formation promoting material C2 was obtained in the same manner as in Example 5 except that self-assembled peptide gel C1 was used. The properties and pH of the gel before adding the born chip, and the properties and pH of the bone formation promoting material C2 were evaluated in the same manner as in Example 5.
  • FIG. 9 A photograph of the gel before the addition of the born chip in Examples 5 to 6 and Comparative Example 2 is shown in FIG. 9, and a photograph of the gel after the born chip is added (the osteogenesis promoting material) is shown in FIG.
  • all the gels before adding the born chip were uniform gels (homogeneous).
  • the bone formation promoting materials of Examples 5 and 6 were observed with a stereomicroscope, they were in a homogeneous state in which the born chips were uniformly dispersed (FIGS. 10A and 10B).
  • the osteogenesis promoting material of Comparative Example 2 gel-like precipitates were confirmed, and the material was in a non-uniform state (heterogeneous) (FIG. 10C).
  • Example 5 the pH was neutral (about pH 6 to 8) before and after the addition of the born chip.
  • Comparative Example 2 the pH of the gel before adding the born chip was acidic (about pH 4), but the pH became neutral (about pH 6 to 8) after the born chip was added.
  • Example 5 since the pH of the gel was maintained before and after the addition of the born chip, the obtained bone formation promoting material maintained a uniform property. In these examples, since the born chips are uniformly dispersed, it is considered that the bone formation promoting material is used as a scaffold and the bone formation rate is improved. On the other hand, in Comparative Example 2, since the gel was in a heterogeneous state due to the change in pH due to the addition of born chip, it is considered that bone formation could not be promoted sufficiently.
  • the bone formation promoting material of the present invention can be suitably used in the fields of research and development and medicine.

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Abstract

　L'invention concerne un promoteur de l'ostéogenèse présentant une grande innocuité biologique et permettant de promouvoir l'ostéogenèse. Le promoteur de l'ostéogenèse de la présente invention comprend un peptide auto-assemblé capable de former une structure de feuillet beta dans une solution aqueuse de pH neutre, et des fragments d'os. La somme de la charge des résidus acides aminés constituant le peptide auto-assemblé à un pH de 7,0 n'est pas 0.
PCT/JP2015/068683 2014-06-30 2015-06-29 Promoteur de l'ostéogenèse WO2016002717A1 (fr)

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CN202310424217.4A CN116603103A (zh) 2014-06-30 2015-06-29 骨形成促进材料
JP2016521805A JP6042038B2 (ja) 2014-06-30 2015-06-29 骨形成促進材
EP15815879.0A EP3162374A4 (fr) 2014-06-30 2015-06-29 Promoteur de l'ostéogenèse
CN201580036020.7A CN106573019A (zh) 2014-06-30 2015-06-29 骨形成促进材料

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